Browsing Theses and Dissertations School of Pharmacy by Subject "CADD"
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Structure-based optimization of small molecule transcription therapy targeting the BCL6 oncoproteinBCL6, a member of the BTB/Zinc finger family of proteins is a transcriptional repressor that is constitutively expressed in over 50% of patients with Diffuse Large B Cell Lymphomas (DLBCL). BCL6 is responsible for the repression of at least 14 different genes linked by roles in B cell activation, differentiation, inflammation, and cell cycle control. Prior to cell differentiation, normal BCL6 encourages apoptosis by repressing expression of anti-apoptotic BCL6 target genes in the germinal center. Specific mutations and translocations in the 5' regulatory region of the BCL6 gene have been implicated in the constitutive expression of BCL6. This results in the aberrant replication of B cells that can escape the germinal center and lead to the formation of lymphomas. Preliminary proof of principle experiments have illustrated that an interaction between the BTB domain of BCL6 and unique regulatory sequences of its critical corepressors NCoR and SMRT are responsible for the mechanism of transcriptional repression of BCL6 at a "lateral groove" motif. Peptides that block the BCL6-SMRT interface kill lymphoma cells in vitro and in vivo, without causing toxicity to normal tissues. Small molecule inhibitors based on the 3D BCL6-SMRT interface were discovered via a target based drug design approach utilizing computer aided chemical database screening. Lead compounds displaying the desired biological activity in biochemical and functional assays were identified and selected for chemical derivation. Over 70 compounds have been developed and synthesized and are currently being evaluated for BCL6 inhibitory activity, as a part of our successive chemical optimization process to improve binding affinity, selectivity, and solubility. Preliminary in vitro studies of our first generations of indolylidene inhibitor compounds have demonstrated that an N-carboxylic acid and nature of the central heterocyclic ring are significant for activity. These results are consistent with CADD results determination of an energetically favorable interaction between the carboxylic charged moieties of lead compounds identified from primary database screens and key Arginine and Histidine residues in the putative binding site of the BCl6 BTB domain. Other CADD identified lead candidates possessing a diarylheterocyclic based scaffold were selected for further optimization to generate a chemically diverse library of molecules for SAR investigation of BTB lateral groove blockade and are presented. As continuation of this work, the development of small molecule inhibitors to target a secondary binding site of the BTB domain is described. Our structure-based strategy for introducing chemical modifications to our existing small molecule inhibitors along with proposed synthetic methodology to develop targets achieving this unique biological profile are reported.